Goldsmith Scott R, Streeter Shawn, Covut Fahrettin
Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd, Duarte, CA, 91010, USA.
Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Curr Hematol Malig Rep. 2022 Dec;17(6):286-297. doi: 10.1007/s11899-022-00675-3. Epub 2022 Aug 27.
Advances in multiple myeloma therapies have greatly improved outcomes for patients living with the disease, although to date there is yet to be a cure. Cellular and immunotherapies, approved or in development, offer the promise of significantly advancing toward that possibility. The aim of this review is to provide a synopsis and commentary on the current and future states of bispecific agents aimed at harnessing the antineoplastic potential of T-cells in treating and eradicating myeloma.
Numerous bispecific agents are in clinical development with some on the precipice of regulatory approval. While BCMA remains the principal target, some agents are directed at novel targets such as GPRC5D and FcRH5. The constructs vary in design and pharmacokinetics which has dosing and administration implications. The toxicity profiles of these agents generally reflect that of other immune therapies, including cytokine release syndrome and rarely neurotoxicity, although immunosuppression has also led to elevated infection risks. However, the toxicities are generally manageable and offset by unprecedented efficacy seen in such heavily pretreated cohorts. Bispecific agents are poised to significantly alter the treatment paradigms for myeloma. They provide a convenient "off-the-shelf" platform with often deep and durable responses. Toxicities are often limited in duration and severity. In the early-phase trials, many patients have been able to remain on treatment for extended periods, even among those with high-risk features. Upcoming trials are likely to explore earlier implementation of these agents in order to offer this therapeutic opportunity to broader cohorts.
尽管目前多发性骨髓瘤仍无法治愈，但该疾病的治疗进展已极大改善了患者的预后。已获批或仍在研发的细胞疗法和免疫疗法有望显著推动治愈该疾病的可能性。本综述旨在对双特异性药物的现状和未来发展进行概述和评论，这些药物旨在利用T细胞的抗肿瘤潜力来治疗和根除骨髓瘤。
众多双特异性药物正处于临床开发阶段，其中一些已接近监管批准阶段。虽然B细胞成熟抗原（BCMA）仍是主要靶点，但一些药物针对的是诸如G蛋白偶联受体C5D（GPRC5D）和Fc段受体同源物5（FcRH5）等新靶点。这些药物的结构在设计和药代动力学方面各不相同，这对给药剂量和方式有一定影响。这些药物的毒性特征通常反映了其他免疫疗法的毒性，包括细胞因子释放综合征，且很少有神经毒性，不过免疫抑制也导致感染风险增加。然而，这些毒性通常是可控的，并且在如此多经过大量预处理的患者队列中所观察到的前所未有的疗效抵消了毒性。双特异性药物有望显著改变骨髓瘤的治疗模式。它们提供了一个便捷的“即用型”平台，通常能产生深度且持久的反应。毒性的持续时间和严重程度往往有限。在早期试验中，许多患者即使是具有高风险特征的患者也能够长期接受治疗。即将开展的试验可能会探索更早应用这些药物，以便将这种治疗机会提供给更广泛的患者群体。
